Periventricular heterotopia (PH) is one of the relatively common malformations of cortical development (MCD) characterized by the abnormal presence of gray matter nodules along the lateral ventricle and late-onset intractable epilepsy. Mutations in the X-linked filamin A (FLNA) gene, which encodes an actin binding protein, are known to be the leading genetic cause of PH. Despite extensive cell molecular studies of filamin A in the past three decades, the developmental mechanism underlying FLNA's role in cerebral cortical neurogenesis and neuronal migration, as well as the pathogenesis of PH, remains elusive. This proposal presents a set of approaches to establish an experimental system to allow FLNA's function in cerebral cortical development to be tested directly. Towards this goal, we generated a mouse model of PH by conditionally eliminating filamin A (Flna) in the developing cortex together with its closely related family member filamin B (Flnb). Preliminary analyses showed that this mouse model recapitulated almost all anatomical features of PH caused by human FLNA mutations. Our developmental studies using this PH model suggested a previously unrecognized role of FLNA in maintaining the structure and organization of neural progenitor domains and the neurogenic niche of neuronal fate restricted intermediate neural progenitors (INPs). Loss of this function leads the mislocalization and extraneous neurogenesis of INPs along the brain ventricles. The three specific aims of this proposal will validate these findings and further investigate the molecular developmental programs governed by filamin by 1) further characterizing anatomical features of the mouse PH brain, 2) determining the developmental processes disrupted by filamin mutations, and 3) identifying the cell molecular functions of filamin in normal and pathological formation of the cerebral cortex. The completion of these aims will not only reveal the pathogenesis of PH, but also provide important insights into mechanisms through which the neurogenic potential may be enhanced in the developing brain. Results from these studies are thus expected to guide the development of neural stem cell based therapies for a wide variety of developmental brain disorders.